JP6364546B2 - Anti-tumor agent side effect reducing agent - Google Patents

Description

  The present invention relates to a side effect reducing agent for an antitumor agent.

  Deoxyuridine triphosphatase (hereinafter also referred to as “dUTPase” (EC 3.6.1.23)) is a prophylactic DNA repair enzyme. An enzyme that specifically recognizes only deoxyuridine triphosphate in natural nucleic acid triphosphates and decomposes it into deoxyuridine monophosphate and pyrophosphate, essential for cell survival in both prokaryotes and eukaryotes. It is known that there is.

In malignant tumors, there is a correlation between the degree of malignancy and the expression level of dUTPase (Non-Patent Documents 1 and 2), and it has been reported that tumors with increased expression show resistance to chemotherapy (Non-patents). Reference 3). In cultured cancer cells, it has been shown that reducing the expression level of dUTPase using siRNA enhances the antitumor effect of a thymidylate synthase inhibitor (hereinafter referred to as “TS inhibitor”) (non-patented). Reference 4).
On the other hand, Patent Document 1 discloses a uracil compound having a dUTPase inhibitory action, and Patent Document 2 discloses that the uracil compound enhances an antitumor effect.

  However, it is not known at all that the uracil compound described above reduces the side effects of antitumor agents.

International Publication No. 2009/147843 International Publication No. 2011/066551

J Clin Pathol. 2009 Apr; 62 (4): 364-9 Int J Cancer. 1999 Dec 22; 84 (6): 614-7 Cancer Res. 2000 Jul 1; 60 (13): 3493-503. Mol Pharmacol. 2004 Sep; 66 (3): 620-6

  The present invention relates to providing a side effect reducing agent for an antitumor agent that reduces side effects of the antitumor agent when used in combination with the antitumor agent.

  As a result of intensive studies to solve the above problems, the present inventors have found that a uracil compound having a sulfonamide structure at the N-1 position of the uracil ring represented by the following formula (I) or a salt thereof is an antitumor agent. Has been found to be useful as a side effect reducing agent of the antitumor agent, and has completed the present invention.

That is, the present invention provides the following [1] to [20].
[1] The following formula (I)

[Wherein, R ¹ represents a hydrogen atom or a C 1-6 alkyl group, R ² represents a hydrogen atom or a halogen atom, R ³ represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group. , (C3-6 cycloalkyl) represents a C1-6 alkyl group, a halogeno C1-6 alkyl group, or a saturated heterocyclic group]
A side effect reducing agent for an antitumor agent, which comprises an uracil compound represented by the formula: or a pharmaceutically acceptable salt thereof as an active ingredient.
[2] The uracil compound is represented by the formula (I), wherein R ¹ is a hydrogen atom, a methyl group or an ethyl group, R ² is a hydrogen atom, R ³ is a cyclopentyl group, a cyclopropylmethyl group, or 2, The side effect reducing agent for an antitumor agent according to [1], which is a compound having a 2,2-trifluoroethyl group.
[3] The anti-tumor agent side effect reducing agent according to [1] or [2], wherein the uracil compound is selected from the following group.
N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide N- (3- (cyclopropylmethoxy) benzyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide. (R) -N- (1- (3- (2,2,2-trifluoroethoxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy ) Propane-1-sulfonamide [4] The antitumor agent side effect reducing agent according to any one of [1] to [3], wherein the antitumor agent is an antimetabolite.
[5] The antitumor agent is any of 5-fluorouracil (5-FU), tegafur, gimeracil, oteracil potassium combination agent (tegafur: gimeracil: oteracil = 1: 0.4: 1 (molar ratio)) and pemetrexed The side effect reducing agent of the antitumor agent according to any one of [1] to [3].
[6] The following formula (I) for producing a side effect reducing agent for an antitumor agent

[Wherein, R ¹ represents a hydrogen atom or a C 1-6 alkyl group, R ² represents a hydrogen atom or a halogen atom, R ³ represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group. , (C3-6 cycloalkyl) represents a C1-6 alkyl group, a halogeno C1-6 alkyl group, or a saturated heterocyclic group]
Or a pharmaceutically acceptable salt thereof.
[7] In the uracil compound, in formula (I), R ¹ is a hydrogen atom, a methyl group or an ethyl group, R ² is a hydrogen atom, R ³ is a cyclopentyl group, a cyclopropylmethyl group, or 2, The use according to [6], which is a compound which is a 2,2-trifluoroethyl group.
[8] The use according to [6], wherein the uracil compound is a compound selected from the following group.
N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide N- (3- (cyclopropylmethoxy) benzyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide. (R) -N- (1- (3- (2,2,2-trifluoroethoxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy The use according to any one of [6] to [8], wherein the propane-1-sulfonamide [9] antitumor agent is an antimetabolite.
[10] The antitumor agent is any of 5-fluorouracil (5-FU), tegafur, gimeracil, and oteracil potassium combination agent (tegafur: gimeracil: oteracil = 1: 0.4: 1 (molar ratio)) and pemetrexed The use according to any one of [6] to [8].
[11] The following formula (I) for use in reducing side effects of antitumor agents

[Wherein, R ¹ represents a hydrogen atom or a C 1-6 alkyl group, R ² represents a hydrogen atom or a halogen atom, R ³ represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group. , (C3-6 cycloalkyl) represents a C1-6 alkyl group, a halogeno C1-6 alkyl group, or a saturated heterocyclic group]
Or a pharmaceutically acceptable salt thereof.
[12] In the formula (I), R ¹ is a hydrogen atom, a methyl group or an ethyl group, R ² is a hydrogen atom, R ³ is a cyclopentyl group, a cyclopropylmethyl group, or 2,2,2-tri The uracil compound or a pharmaceutically acceptable salt thereof according to [11], which is a fluoroethyl group.
[13] The uracil compound or a pharmaceutically acceptable salt thereof according to [11], which is a compound selected from the following group or a pharmaceutically acceptable salt thereof.
N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide N- (3- (cyclopropylmethoxy) benzyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide. (R) -N- (1- (3- (2,2,2-trifluoroethoxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy ) The uracil compound or pharmaceutically acceptable salt thereof according to any one of [11] to [13], wherein the propane-1-sulfonamide [14] antitumor agent is an antimetabolite.
[15] The antitumor agent is any of 5-fluorouracil (5-FU), tegafur, gimeracil, and oteracil potassium combination agent (tegafur: gimeracil: oteracil = 1: 0.4: 1 (molar ratio)) and pemetrexed [11] to [13], wherein the uracil compound or a pharmaceutically acceptable salt thereof.
[16] A method for reducing side effects of an antitumor agent, wherein the subject is in need of the following formula (I)

[Wherein, R ¹ represents a hydrogen atom or a C 1-6 alkyl group, R ² represents a hydrogen atom or a halogen atom, R ³ represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group. , (C3-6 cycloalkyl) represents a C1-6 alkyl group, a halogeno C1-6 alkyl group, or a saturated heterocyclic group]
A method comprising administering an effective amount of a uracil compound represented by: or a pharmaceutically acceptable salt thereof.
[17] In the uracil compound, in formula (I), R ¹ is a hydrogen atom, a methyl group or an ethyl group, R ² is a hydrogen atom, R ³ is a cyclopentyl group, a cyclopropylmethyl group, or 2, The method according to [16], which is a compound which is a 2,2-trifluoroethyl group.
[18] The method according to [16], wherein the uracil compound is selected from the following group.
N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide N- (3- (cyclopropylmethoxy) benzyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide. (R) -N- (1- (3- (2,2,2-trifluoroethoxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy ) The method according to any one of [16] to [18], wherein the propane-1-sulfonamide [19] antitumor agent is an antimetabolite.
[20] The antitumor agent is any of 5-fluorouracil (5-FU), tegafur, gimeracil, and oteracil potassium combination agent (tegafur: gimeracil: oteracil = 1: 0.4: 1 (molar ratio)) and pemetrexed The method according to any one of [16] to [18].

  By using the anti-tumor agent side effect reducing agent of the present invention in combination with the anti-tumor agent, side effects of the anti-tumor agent such as gastrointestinal toxicity can be reduced. Therefore, according to the present invention, it is possible to provide cancer chemotherapy with higher safety, and it is also possible to administer an increased amount of an antitumor agent, thereby providing cancer chemotherapy with higher therapeutic effect. Is possible.

It is a figure which shows the weight change rate with respect to Pemetrex in a cancer bearing mouse | mouth. It is a figure which shows the diarrhea expression rate with respect to Pemetrex in a cancer bearing mouse | mouth. It is a figure which shows the weight change rate with respect to S-1 in a tumor bearing mouse | mouth. It is a figure which shows the weight change rate with respect to S-1 in a tumor bearing mouse | mouth. It is a figure which shows the diarrhea expression rate with respect to S-1 in a cancer bearing mouse | mouth. It is a figure which shows the body weight change rate with respect to S-1 in a non-cancer bearing mouse | mouth. It is a figure which shows the diarrhea expression rate with respect to S-1 in a non-cancer bearing mouse | mouth. It is a figure which shows the body weight change rate with respect to FCD in a non-cancer-bearing mouse | mouth. It is a figure which shows the diarrhea expression rate with respect to FCD in a non-cancer bearing mouse | mouth.

In the formula (I), examples of the “C 1-6 alkyl group” represented by R ¹ include a linear or branched hydrocarbon group having 1 to 6 carbon atoms, specifically a methyl group, Examples include an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an n-hexyl group, and a C1-3 alkyl group is preferable, and a methyl group An ethyl group is more preferable.
In the formula (I), the “halogen atom” represented by R ² is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom.
In the formula (I), R ² is preferably a hydrogen atom.
In the formula (I), examples of the “C 1-6 alkyl group” represented by R ³ include the same as those described above for R ¹ .

In the formula (I), “C2-6 alkenyl group” represented by R ³ represents a hydrocarbon group having 2 to 6 carbon atoms including a carbon-carbon double bond, vinyl group, allyl group, methylvinyl. Group, propenyl group, butenyl group, pentenyl group, hexenyl group and the like.
In the formula (I), examples of the “C 3-6 cycloalkyl group” represented by R ³ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like, preferably a cyclopentyl group.
In the formula (I), “(C 3-6 cycloalkyl) C 1-6 alkyl group” represented by R ³ represents an alkyl group having 1 to 6 carbon atoms having the above cycloalkyl group, preferably cyclopropyl It is a methyl group.

In the formula (I), “halogeno C 1-6 alkyl group” represented by R ³ represents an alkyl group having 1 to 6 carbon atoms having the above halogen atom, preferably 2,2,2-trifluoroethyl. It is a group.
In the formula (I), the “saturated heterocyclic group” represented by R ³ is preferably monocyclic or bicyclic having one or two oxygen atoms, nitrogen atoms or sulfur atoms. A cyclic saturated heterocyclic group is exemplified, and examples thereof include pyrrolidinyl group, piperidinyl group, piperazinyl group, hexamethyleneimino group, morpholino group, thiomorpholino group, homopiperidinyl group, tetrahydrofuryl group, tetrahydropyryl group and the like.
R ³ is preferably a cyclopentyl group, a cyclopropylmethyl group, or a 2,2,2-trifluoroethyl group.

In formula (I), R ¹ represents a hydrogen atom, a methyl group or an ethyl group; R ² represents a hydrogen atom; R ³ represents a cyclopentyl group, a cyclopropylmethyl group, or a 2,2,2-trifluoroethyl group. Is preferable.

  Pharmaceutically acceptable salts of the uracil compound represented by the formula (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propion Acid addition with organic acids such as acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, paratoluenesulfonic acid, glutamic acid Examples include salts, ammonium salts with inorganic bases such as salts, sodium, potassium, magnesium, calcium and aluminum, organic bases such as methylamine, ethylamine, meglumine and ethanolamine, or basic amino acids such as lysine, arginine and ornithine. It is done. The uracil compound represented by the formula (I) includes optical isomers and hydrates.

  The uracil compound represented by the formula (I) of the present invention can be produced according to Patent Document 1 or Patent Document 2.

As shown in Examples described later, the uracil compound represented by the formula (I) has an action of reducing side effects of the antitumor agent when used in combination with various antitumor agents.
Therefore, the uracil compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be used as a side effect reducing agent for an antitumor agent.
The uracil compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be used for administering an effective amount thereof and reducing the side effects of the antitumor agent.
Further, the uracil compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be used for producing a side effect reducing agent for an antitumor agent.

  In the present invention, “reducing side effects of an antitumor agent” refers to a side effect caused by the antitumor agent when a uracil compound represented by formula (I) or a pharmaceutically acceptable salt thereof is used in combination with the antitumor agent. Means to reduce.

  Here, examples of the “side effects” include symptoms that appear when normal cells such as hematopoietic cells, oral mucosa, gastrointestinal mucosa, and hair root cells are damaged by an antitumor agent. For example, hematopoietic cells are damaged. Symptoms include anemia, infection, bleeding, hair loss caused by damaged root cells, stomatitis caused by damaged oral mucosa, nausea and diarrhea caused by damaged gastrointestinal mucosa (gastrointestinal toxicity) It is done. Of these, it is more effective against gastrointestinal toxicity and is particularly effective against diarrhea.

  The antitumor agent whose side effects are reduced by the side effect reducing agent of the antitumor agent of the present invention is not particularly limited. For example, alkylating agents such as cyclophosphamide and nimustine, platinum such as cisplatin, carboplatin, and oxaliplatin Formulations; antimetabolites; plant alkaloid antitumor agents such as paclitaxel, docetaxel, irinotecan, and the like, preferably antimetabolites.

Here, an antimetabolite is a compound having a chemical structure similar to that of a substance used as a nucleic acid material when cancer cells divide or proliferate, or a drug containing the same as an active ingredient, and biosynthesis of nucleic acid. Alternatively, it refers to an anticancer agent that inhibits the biosynthetic pathway of nucleic acids and suppresses proliferation. For example, 5-fluorouracil (5-FU), tegafur, gimeracil, oteracil potassium combination agent (tegafur: gimeracil: oteracil = 1: 0.4: 1 (molar ratio); hereinafter, “S-1”), tegafur uracil Combination drug (tegafur: uracil = 1: 4; hereinafter “UFT”), capecitabine, doxyfluridine, 5-fluoro-2′-deoxyuridine (FdUrd), pyrimidine antimetabolite such as gemcitabine, cytarabine, fludarabine, cladribine, nelarabine Purine antimetabolites such as folate antimetabolites such as pemetrexed and methotrexate.
Of these, thymidylate (TMP) synthesis pathway inhibitors are preferred. A thymidylate synthesis pathway inhibitor is an antimetabolite, such as a thymidylate synthase inhibitor or a dihydrofolate reductase inhibitor, which directly or indirectly inhibits an enzyme involved in TMP biosynthesis. Or a drug containing the same as an active ingredient. A thymidylate synthase inhibitor refers to a compound that inhibits thymidylate synthase or a drug containing the same as an active ingredient, such as 5-fluorouracil (5-FU), S-1, UFT, capecitabine, doxyfluridine, 5 -Fluoropyrimidine antimetabolites such as fluoro-2'-deoxyuridine (FdUrd) and Carmofur (Yamafur), antifolates such as pemetrexed, methotrexate and raltitrexed, and nolatrexed dihydrochloride. The dihydrofolate reductase inhibitor refers to an inhibitor compound of an enzyme that biosynthesizes tetrahydrofolate essential for de novo synthesis, such as purines and thymidylate, or a drug containing it as an active ingredient, for example, plalatrexate And antifolate inhibitors such as edatrexate, pyrimesamine, brodimoprim, and trimethrexate glucuronate.
As an antitumor agent whose side effects are reduced by the side effect reducing agent of the antitumor agent of the present invention, a thymidylate synthase inhibitor is more preferable, a drug containing tegafur / gimeracil as an active ingredient, pemetrexed is more preferable, S-1 and pemetrexed are particularly preferred.
Further, the malignant tumor that can be treated when the anti-tumor agent side effect reducing agent of the present invention is used in combination with the above-described anti-tumor agent is not particularly limited, but for example, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, Liver cancer, gallbladder / bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple Examples include myeloma, skin cancer, and brain tumor.

  By using the anti-tumor agent side effect reducing agent of the present invention in combination with the anti-tumor agent, it is possible to provide cancer chemotherapy in which the side effect of the anti-tumor agent is reduced. In this case, the side effect reducing agent of the antitumor agent of the present invention may be a one-form preparation form containing an antitumor agent, and the side effect reducing agent of the antitumor agent of the present invention is an antitumor agent. It may be formulated separately and used in combination at the time of use.

  When the side effect reducing agent of the antitumor agent of the present invention and the antitumor agent are used in separate forms, the administration means of the side effect reducing agent of the antitumor agent of the present invention and the administration means of the antitumor agent may be the same. However, they may be different (for example, oral administration and injection). Moreover, the administration time of the side effect reducing agent and the antitumor agent of the antitumor agent may be the same or may be administered at an interval, and the administration order of both is not limited and can be appropriately selected. Preferably, the other is administered at the same time or within 6 hours after administration of one.

  When the side effect reducing agent and antitumor agent of the antitumor agent of the present invention are used in separate forms, they can be provided in the form of a “kit”. That is, the side effect reducing agent and the antitumor agent of the antitumor agent of the present invention are each in an arbitrary preparation form, and are stored in various commonly used containers according to the preparation form, and cancer in mammals including humans. It can be a therapeutic kit.

The side effect reducing agent of the antitumor agent of the present invention is used as a medicine (pharmaceutical composition). In this case, in addition to the uracil compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, it is necessary. Depending on the type of pharmaceutical carrier, various dosage forms can be prepared depending on the purpose of prevention or treatment.
Examples of the form include oral preparations, injections, suppositories, ointments, patches, and the like, and oral preparations are preferable. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.

  As the pharmaceutical carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, binders, disintegrants, lubricants, colorants in solid preparations; solvents, dissolution aids, suspensions in liquid preparations. It is blended as a turbidity agent, tonicity agent, buffering agent, soothing agent and the like. Moreover, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers and the like can be used as necessary.

  When preparing an oral solid preparation, the uracil compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is mixed with an excipient, and if necessary, a binder, a disintegrant, a lubricant, After adding a colorant, a flavoring / flavoring agent, etc., tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods.

  Here, examples of the excipient include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid. As binders, water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, α-starch solution, gelatin solution, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, Shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol. Examples of the colorant include titanium oxide and iron oxide. Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.

  When preparing an oral liquid preparation, add a flavoring agent, buffering agent, stabilizer, flavoring agent, etc. to the uracil compound represented by formula (I) or a pharmaceutically acceptable salt thereof by a conventional method. Internal liquids, syrups, elixirs and the like can be produced. In this case, the flavoring / flavoring agent may be those listed above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin. If necessary, an enteric coating or a coating can be applied to the oral preparation by a known method for the purpose of sustaining the effect. Examples of such a coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80 (registered trademark), and the like.

  When preparing an injection, a uracil compound represented by formula (I) or a pharmaceutically acceptable salt thereof is added with a pH adjuster, a buffer, a stabilizer, an isotonic agent, a local anesthetic, and the like. In addition, subcutaneous, intramuscular and intravenous injections can be produced by conventional methods. In this case, examples of the pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride, glucose, D-mannitol, glycerin and the like.

  When preparing a suppository, a uracil compound represented by formula (I) or a pharmaceutically acceptable salt thereof is added to a pharmaceutical carrier known in the art such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride. Can be produced by a conventional method after adding a surfactant such as Tween 80 (registered trademark), if necessary.

  When preparing an ointment, a commonly used base, stabilizer, wetting agent, preservative, etc., may be added to the uracil compound represented by formula (I) or a pharmaceutically acceptable salt thereof as necessary. They are blended and mixed and formulated by conventional methods. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.

  When preparing a patch, the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method. As the support, a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane film or foam sheet made of cotton, suf, chemical fiber is suitable.

The amount of the uracil compound represented by formula (I) or a pharmaceutically acceptable salt thereof to be blended in each of the above dosage unit forms depends on the symptoms of the patient to which it is applied, its dosage form, etc. However, it is generally about 0.05 to 1000 mg for oral preparations, about 0.01 to 500 mg for injections, and about 1 to 1000 mg for suppositories per dosage unit form.
In addition, the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally. It is about 5000 mg, preferably 0.1 to 1000 mg, and is preferably administered once a day or divided into 2 to 3 times a day.

  Since the side effect of the antitumor agent can be reduced by using the side effect reducing agent of the antitumor agent of the present invention, the dose of the antitumor agent may be a commonly used dose, but a commonly used dose It can also be used in an increased amount.

  The administration or blending ratio of the side effect reducing agent and the antitumor agent of the antitumor agent of the present invention is not particularly limited as long as the antitumor effect is enhanced, but the formula ( The uracil compound represented by I) or a pharmaceutically acceptable salt thereof may be about 0.01 to 100 mol, preferably about 0.07 to 64 mol. Here, the administration or blending ratio of the antitumor agent is based on the amount of the active ingredient exhibiting the antitumor effect. For example, in the case of a drug containing tegafur and gimeracil, the uracil compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 0.01 to 100 per 1 mol of tegafur as a daily dose. About a mole, preferably about 0.15 to 64 mole. In the case of pemetrexed, the uracil compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is about 0.01 to 100 mol, preferably about 0.07 to 12 mol, per 1 mol of pemetrexed. And it is sufficient.

  EXAMPLES Examples and test examples will be shown below to describe the present invention in more detail, but the present invention is not limited to these examples.

Example 1
(R) -N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1 -Synthesis of sulfonamide The sulfonamide was synthesized according to the method disclosed in Patent Document 1.
¹ H-NMR (CDCl 3): δ ppm 1.53 (3H, d, J = 6.8 Hz), 1.56-1.98 (10H, m), 2.67-2.78 (1H, m), 2.80-2.91 (1H, m), 3.42-3.60 (2H, m), 4.51-4.63 (1H, m), 4.74-4.89 (2H, m ), 5.05 (2H, s), 5.76 (1H, dd, J = 7.8 Hz, 2.2 Hz), 6.77-6.89 (3H, m), 7.20-7.27. (2H, m), 8.76 (1H, brs): LRMS (ESI) m / z 452 [M + H]

Example 2
Synthesis of N- (3- (cyclopropylmethoxy) benzyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide Patent Document 1 It was synthesized according to the method disclosed in 1.
¹ H-NMR (CDCl 3) δ (ppm): 0.30-0.39 (2H, m), 0.57-0.68 (2H, m), 1.20-1.31 (1H, m) 1.96-2.09 (2H, m), 3.0 (2H, t, J = 7.2 Hz), 3.57-3.64 (2H, m), 3.81 (2H, d, J = 6.9 Hz), 4.25 (2H, d, J = 6.1 Hz), 4.89 (1H, brs), 5.09 (2H, s), 5.75 (1H, dd, J = 7.9, 1.8 Hz), 6.76-6.90 (3H, m), 7.20-7.29 (2H, m), 8.90 (1H, brs)

Example 3
(R) -N- (1- (3- (2,2,2-trifluoroethoxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidine-1 (2H)- Synthesis of yl) methoxy) propane-1-sulfonamide Synthesis was performed according to the method disclosed in Patent Document 1.
¹ H-NMR (DMSO-D6) δ (ppm): 1.37 (3H, d, J = 6.8 Hz), 1.69-1.80 (2H, m), 2.58-2.70 ( 1H, m), 2.72-2.88 (1H, m), 3.31-3.46 (2H, m), 4.39-4.45 (1H, m), 4.69-4. 79 (2H, m), 4.99 (2H, s), 5.60 (1 H, dd, J = 8.1, 0.8 Hz), 6.91-7.08 (3H, m), 7. 26-7.31 (1H, m), 7.63 (1H, dd, J = 8.1, 0.8 Hz), 7.73 (1H, d, J = 8.6 Hz), 11.3 (1H , Brs)

Test example 1
Toxicity mitigating effect on pemetrexed Human lung cancer strain NCI-H441 was suspended in PBS containing 50% matrigel, and 8 × ⁶ BALB / cA Jcl-nu mice (CLEA Japan, Inc.) 5 × 10 ⁶ cells / cell subcutaneously on the right chest. Transplanted at 0.1 mL / body. When the average tumor volume after grouping exceeded 100 mm ³ , the major axis and minor axis of the tumor were measured, and grouping was performed so that there was no variation in the tumor volume of each group (6 mice per group). Moreover, it implemented on the conditions under the low folic acid feed breeding from the age of 5 weeks to the test end date.
Pemetrexed (manufactured by LC Laboratories Co., Ltd.) was dissolved in physiological saline and administered via the caudal vein on the first day after grouping and on the eighth day after one week. Compound 1 was suspended in a 0.5% hydroxypropylmethylcellulose aqueous solution and orally administered once a day for 14 days once a day from the next day of grouping. The Pemetrexed dose was 50 mg / kg / day and the Compound 1 dose was 600 mg / kg / day.
The body weight (Body weight, BW) was measured twice a week from the grouping, and the body weight change rate (Body weight change, BWC) was calculated from the following formula to determine the toxicity reduction effect.

(Formula 1) BWC (%) = [BW− (BW on day 0)] / (BW on day 0) × 100
[In the formula, BWC indicates the weight change rate, BW indicates the weight on each measurement day, and BW on day 0 indicates the weight on the grouping day. ]

  The test results are shown in FIG. While weight loss was significant with the Pemetrexed single agent, weight loss was suppressed by using the compound of the present invention in combination.

Also, on the 15th day from the start of drug administration, the presence of diarrhea was confirmed by observing the vicinity of the anus of the mouse for each individual, and the rate of diarrhea symptoms in each group was calculated as the diarrhea incidence (%) Then, the gastrointestinal toxicity reduction effect was determined.
The test results are shown in FIG. In the case of Pemetrexed alone, diarrhea was observed at a frequency of 60%, whereas no diarrhea was observed when the compound of the present invention was used in combination.
Furthermore, the number of dead individuals during the test is shown in Table 2. In Pemetrexed single agent, 1 of 6 deaths was observed, but no death was confirmed by using the compound of the present invention in combination.
From the above, it has been clarified that the compound of the present invention reduces the side effects of Pemetrexed.

Test example 2
Toxicity-reducing effect on S-1 Human breast cancer strain MX-1 subcultured subcutaneously was made into a 2 mm square fragment and transplanted subcutaneously into the right breast of 5 or 6-week-old BALB / cA Jcl-nu mice (Claire Japan). . When the average tumor volume after grouping exceeded 100 mm ³ , the major axis and minor axis of the tumor were measured, and grouping was performed so that there was no variation in the tumor volume of each group (5 per group).
S-1 <manufactured by Taiho Pharmaceutical Co., Ltd.> and a test compound were suspended in a 0.5% hydroxypropylmethylcellulose aqueous solution and orally administered once a day for 14 days once a day from the next day of grouping. The dose of S-1 was 8.3 mg / kg / day, which is expected to be effective. The test compound (compounds 2 and 3) was administered at a dose of 75, 100, 150, 300 or 600 mg / kg / day and administered simultaneously with S-1.
The body weight (Body weight, BW) was measured twice a week from the grouping, and the body weight change rate (Body weight change, BWC) was calculated from the following formula to determine the toxicity reduction effect.

(Formula 1) BWC (%) = [BW− (BW on day 0)] / (BW on day 0) × 100
[In the formula, BWC indicates the weight change rate, BW indicates the weight on each measurement day, and BW on day 0 indicates the weight on the grouping day. ]

  The test results are shown in FIGS. While weight loss was observed with the S-1 single agent, weight loss was suppressed by using the compound of the present invention in combination.

15 days after the start of drug administration, the presence or absence of diarrhea was confirmed by observing the vicinity of the anus of the mouse for each individual, and the ratio of diarrhea symptoms observed in each group was calculated as the diarrhea incidence (%). Gastrointestinal toxicity reduction effect was determined.
The test results are shown in FIG. In the S-1 single agent, diarrhea was observed at a frequency of 80% or more, whereas the combined use of the compound of the present invention decreased diarrhea in a dose-dependent manner.

Further, the number of dead individuals during the test is shown in Table 3. In the S-1 single agent, 1 case of death was observed in 5 cases, but no case of death was confirmed by using the compound of the present invention in combination.
From the above, it was revealed that the compound of the present invention reduces the side effects of S-1.

Test example 3
Toxicity-reducing effect on S-1 After measuring the weight of 6-week-old BALB / cA Jcl-nu mice (CLEA Japan, Inc.), stratified randomly so that the weight of each group after grouping becomes uniform The grouping was performed according to the chemical formula (5 per group).
S-1 <manufactured by Taiho Pharmaceutical Co., Ltd.> and a test compound were suspended in a 0.5% hydroxypropylmethylcellulose aqueous solution and orally administered once a day for 14 days once a day from the next day of grouping. The dose of S-1 was a toxic dose of 12 mg / kg / day. The test compound (compound 1) was administered at a dose of 300 or 600 mg / kg / day and administered simultaneously with S-1.
The body weight (Body weight, BW) was measured twice a week from the grouping, and the body weight change rate (Body weight change, BWC) was calculated from the following formula to determine the toxicity reduction effect.

(Formula 1) BWC (%) = [BW− (BW on day 0)] / (BW on day 0) × 100
[In the formula, BWC indicates the weight change rate, BW indicates the weight on each measurement day, and BW on day 0 indicates the weight on the grouping day. ]

  The test results are shown in FIG. Weight loss was observed with S-1 alone (note that, as shown in Table 3, 2 out of 5 cases showed significant weight loss and died around the 10th day, so the average weight in the weight measurement after the 12th day increased. doing). By using the compound of the present invention in combination, weight loss was suppressed in a dose-dependent manner.

In addition, the presence of diarrhea was confirmed by observing the vicinity of the anus of each mouse for 14 days every day from the start of drug administration, and the percentage of diarrhea symptoms observed in each group was calculated as the diarrhea incidence (%). Then, the gastrointestinal toxicity reduction effect was determined.
The test results are shown in FIG. In the S-1 single agent, diarrhea was frequently observed during the administration period, and on the 8th to 10th days, diarrhea was observed at a frequency of 100%. On the other hand, the frequency of diarrhea decreased in a dose-dependent manner by using the compound of the present invention in combination.

  Furthermore, the number of dead individuals during the test is shown in Table 4. In S-1 alone, 2 death cases were observed in 5 cases, but the death cases decreased in a dose-dependent manner by using the compound of the present invention in combination. From the above, it was revealed that the compound of the present invention reduces the side effects of S-1.

Test example 4
Toxicity-reducing effect on S-1 For human tumor patients, multiple clinical trials in which S-1 was administered alone and multiple clinical trials in which S-1 and Compound 1 were administered in combination were conducted.
CTCAE was used to evaluate the severity of diarrhea that occurred in patients during the period from the start of the clinical trial to the termination of the trial according to the withdrawal criteria (exacerbation of the primary disease, withdrawal of patient consent).
In clinical trials, in principle, S-1 was administered after meals at a dose of 30 mg / m ² . However, in clinical trials in which S-1 is administered alone, in addition to three trials in which S-1 is administered at a dose of 30 mg / m ² , a plurality of trials in which it is administered after meals at a dose of 36 mg / m ² are conducted. As a result of these tests as a whole (total N number is 1800), the incidence of diarrhea was determined. Incidentally, those administered at a dose of 36 mg / m ² is, AUC _0-12 of the 5-FU that was administered after a meal at a dose of 30 mg / m ² is approximately equal.
Compound 1 was administered simultaneously with S-1.
The incidence of diarrhea of all grades (All) and grade 3 (G3) or higher in patients who combined S-1 alone and S-1 with Compound 1 was compared, and the results are shown in Table 5.
In patients treated with S-1 alone, the incidence of diarrhea in all grades and grades 3 and above was 29.6 to 49% and 3.6 to 21%, whereas S-1 and Compound 1 were used in combination. Those who were administered were 18.8% and 19%, and 0% and 1.6%, and the incidence of diarrhea was reduced by combining the compounds of the present invention.
From the above, it was revealed that the compound of the present invention reduces the side effects of S-1.

Test Example 5
FCD toxicity reduction effect Of tegafur, gimeracil, and oteracil, which are components of S-1, FCD (Tegafur and Tegafur, excluding oteracil (Jpn J Clin Oncol 2009: 39 (1) 2-15) contributing to gastrointestinal tract reduction) The effect of reducing toxicity using gimeracil = 1: 0.4 (molar ratio) was examined.
After weighing 6-week-old BALB / cA Jcl-nu mice (CLEA Japan, Inc.), grouping was performed by random stratification so that the weight of each group after grouping would be uniform (5 per group).
FCD was suspended in 0.5% hydroxypropylmethylcellulose aqueous solution and orally administered once a day for 14 days once a day from the next day of grouping. The FCD dose was 10 mg / kg / day in terms of tegafur. The dose of Compound 1 was 150, 300 or 600 mg / kg / day, and was administered simultaneously with FCD.
The body weight (Body weight, BW) was measured twice a week from the grouping, and the body weight change rate (Body weight change, BWC) was calculated from the following formula to determine the toxicity reduction effect.

(Formula 1) BWC (%) = [BW− (BW on day 0)] / (BW on day 0) × 100
[In the formula, BWC indicates the weight change rate, BW indicates the weight on each measurement day, and BW on day 0 indicates the weight on the grouping day. ]
The test results are shown in FIG. While weight loss was observed with the FCD alone, weight loss was suppressed by using the compound of the present invention in combination.

In addition, the presence of diarrhea was confirmed by observing the vicinity of the anus of each mouse for 14 days every day from the start of drug administration, and the percentage of diarrhea symptoms observed in each group was calculated as the diarrhea incidence (%). Then, the gastrointestinal toxicity reduction effect was determined.
The test results are shown in FIG.
In the FCD single agent, diarrhea was frequently observed during the administration period, and on the 10th day, diarrhea was observed at a frequency of 100%. On the other hand, the frequency of diarrhea decreased in a dose-dependent manner by using the compound of the present invention in combination.
From the above, it has been clarified that the compound of the present invention reduces the side effects of drugs containing tegafur and gimeracil as active ingredients.

Claims (10)

Formula (I)

[Wherein, R ¹ represents a hydrogen atom or a C 1-6 alkyl group, R ² represents a hydrogen atom or a halogen atom, R ³ represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group. , (C3-6 cycloalkyl) represents a C1-6 alkyl group, a halogeno C1-6 alkyl group, or a saturated heterocyclic group]
A side effect reducing agent for an antitumor agent comprising a uracil compound represented by the formula: or a pharmaceutically acceptable salt thereof as an active ingredient. In the formula (I), R ¹ is a hydrogen atom, a methyl group or an ethyl group, R ² is a hydrogen atom, R ³ is a cyclopentyl group, a cyclopropylmethyl group, or 2,2,2 in the formula (I). The side effect reducing agent of the antitumor agent according to claim 1, which is a compound having a -trifluoroethyl group. The side effect reducing agent of the antitumor agent according to claim 1, wherein the uracil compound is selected from the following group.
N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide N- (3- (cyclopropylmethoxy) benzyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide. (R) -N- (1- (3- (2,2,2-trifluoroethoxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy ) Propane-1-sulfonamide   The side effect reducing agent for an antitumor agent according to any one of claims 1 to 3, wherein the antitumor agent is an antimetabolite.   The antitumor agent is any of 5-fluorouracil (5-FU), tegafur, gimeracil, and oteracil potassium combination agent (tegafur: gimeracil: oteracil = 1: 0.4: 1 (molar ratio)) and pemetrexed The side effect reducing agent of the antitumor agent of any one of Claims 1-3. The following formula (I) for producing a side effect reducing agent for an antitumor agent

[Wherein, R ¹ represents a hydrogen atom or a C 1-6 alkyl group, R ² represents a hydrogen atom or a halogen atom, R ³ represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group. , (C3-6 cycloalkyl) represents a C1-6 alkyl group, a halogeno C1-6 alkyl group, or a saturated heterocyclic group]
Or a pharmaceutically acceptable salt thereof. In the formula (I), R ¹ is a hydrogen atom, a methyl group or an ethyl group, R ² is a hydrogen atom, R ³ is a cyclopentyl group, a cyclopropylmethyl group, or 2,2,2 in the formula (I). 7. Use according to claim 6, which is a compound which is a trifluoroethyl group. The use according to claim 6, wherein the uracil compound is a compound selected from the following group.
N- (1- (3- (cyclopentyloxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide N- (3- (cyclopropylmethoxy) benzyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy) propane-1-sulfonamide. (R) -N- (1- (3- (2,2,2-trifluoroethoxy) phenyl) ethyl) -3-((2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl) methoxy ) Propane-1-sulfonamide   The use according to any one of claims 6 to 8, wherein the antitumor agent is an antimetabolite.   The antitumor agent is any of 5-fluorouracil (5-FU), tegafur, gimeracil, and oteracil potassium combination agent (tegafur: gimeracil: oteracil = 1: 0.4: 1 (molar ratio)) and pemetrexed Use according to any one of claims 6-8.

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